WO2004017998A2 - Topical emulsion- gel composition comprising diclofenac sodium - Google Patents

Topical emulsion- gel composition comprising diclofenac sodium Download PDF

Info

Publication number
WO2004017998A2
WO2004017998A2 PCT/EP2003/009302 EP0309302W WO2004017998A2 WO 2004017998 A2 WO2004017998 A2 WO 2004017998A2 EP 0309302 W EP0309302 W EP 0309302W WO 2004017998 A2 WO2004017998 A2 WO 2004017998A2
Authority
WO
WIPO (PCT)
Prior art keywords
composition
composition according
amount
emulsion
gel
Prior art date
Application number
PCT/EP2003/009302
Other languages
French (fr)
Other versions
WO2004017998A3 (en
Inventor
Michel Steiger
Original Assignee
Novartis Consumer Health S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=31896841&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2004017998(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to DK03792412T priority Critical patent/DK1536836T3/en
Priority to AU2003264086A priority patent/AU2003264086B2/en
Priority to EP03792412A priority patent/EP1536836B1/en
Priority to US10/524,735 priority patent/US7732489B2/en
Priority to CA2496469A priority patent/CA2496469C/en
Application filed by Novartis Consumer Health S.A. filed Critical Novartis Consumer Health S.A.
Priority to BR0313701-5A priority patent/BR0313701A/en
Priority to DE60319997T priority patent/DE60319997T2/en
Priority to SI200331225T priority patent/SI1536836T1/en
Priority to MXPA05002077A priority patent/MXPA05002077A/en
Publication of WO2004017998A2 publication Critical patent/WO2004017998A2/en
Publication of WO2004017998A3 publication Critical patent/WO2004017998A3/en
Priority to US12/778,322 priority patent/US8557870B2/en
Priority to US14/053,176 priority patent/US8716340B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds

Definitions

  • the invention concerns topical formulations comprising the well-known and widely used non- steroidal anti-inflammatory drug (NSAID) diclofenac. It is one object of the present invention to provide an advantageous emulsion-gel specifically comprising the sodium salt of diclofenac, diclofenac Na. The latter represents the most simple, cheapest, most often used (taking into account oral and other routes of administration) and best studied derivative of diclofenac.
  • NSAID non-steroidal anti-inflammatory drug
  • a "true" emulsion-gel should be provided wherein diclofenac is fully dissolved (with no identifiable crystals of diclofenac being present in the formulation; see Test example 2 below) rather than partly suspended. This is crucial to guarantee a high, constant and reproducible permeation of diclofenac through the skin.
  • the invention is further characterized in that the beneficial topical formulations provided do include diclofenac, and diclofenac Na specifically, in unusually low amounts only ( ⁇ 0.5%, w/w). Said low dose formulations are particularly advantageous in the topical treatment of burns including sunburn. They are providing similar relief and healing as normal dose formulations (e.g. 1%) but lead to much lower exposure of the body to the active substance.
  • the invention relates to a pharmaceutical composition intended for topical use, which composition is in the form of an opaque emulsion-gel and which composition comprises
  • glycol solvent selected from the group consisting of propylene glycol and polyethylene glycol (200-20000),
  • a basic agent selected from the group consisting of ammonia, sodium hydroxide and potassium hydroxide to adjust the pH of the total composition to 6.5-8.
  • said composition is devoid of any antifungal drug, e.g. devoid of terbinafine and topically acceptable salts thereof.
  • said composition is devoid of any further pharmaceutically active substance, that is to say, diclofenac sodium salt (a) is the only pharmaceutically active substance being present in that case. All percentages given are percentages by weight (w/w), if not indicated otherwise.
  • (c) is present in an amount of from 5 up to 25% and (d) is present in an amount of from 3 up to 7%, of the total composition. In another embodiment of the invention, (c) is present (or not, respectively) in an amount of from 0 up to 5%, in particular 0%, and (d) is present in an amount of from 3 up to 20% of the total composition.
  • (c) is present in an amount of from 0 up to 5% and (d) is present in an amount of from 3 up to 7% of the total composition.
  • Said emulsion-gels have the additional advantage of being perceived by patients as very pleasant and non-sticky on the skin in consumer tests. Said advantage is especially pronounced, if said compositions, in addition, comprise as component (f) isopropyl myristate, and in particular a mixture of isopropyl myristate and C6-C12-alkanoic acid C12-C18-alkyl esters.
  • diclofenac Na (a) is present in amount of from 0.05 up to 0.3% - especially of from 0.1 up to 0.25% - of the total composition.
  • Water (b) is preferably present in an amount of from 50 up to 92%, in particular of from 60 up to 90%, or of from 60 up to 80%, of the total composition.
  • C2-C4-alkanols (c) are ethanol, isopropanol, or mixtures thereof; and in particular isopropanol.
  • (c) is present in an amount of from 0 up to 25%, in particular of from 0 up to 20%, of the total composition.
  • (c) is typically present in an amount of from 5 up to 25%, and in particular of from 10 up to 20%, of the total composition.
  • (c) is present (or not, respectively) in an amount of from 0 up to 5% - preferably of from 0 up to 4%, more preferably of from 0 up to 3%, especially of from 0 up to 2%, and more especially of from 0 up to 1 % - of the total composition.
  • the glycol solvent (d) is propylene glycol.
  • Propylene glycol is 1 ,2-propanediol.
  • polyethylene glycol (200-20000) may be used as (d), preferably polyethylene glycol (200-1000).
  • the glycol solvent (d) is preferably present in an amount of from 3.5 up to 20%, and in particular of from 4 up to 18%, of the total composition.
  • (d) is typically present in an amount of from 3 up to 7%, and in particular of from 3.5 up to 6%, of the total composition.
  • (d) is present in an amount of from 3 up to 20%, especially of from 4 up to 18%, of the total composition.
  • Carbomers in the context of the present invention, are defined as homo- or copolymers of acrylic acid that are cross-linked, e.g. with an allyl ether of pentaerythritol (allyl pentaerythritol) or an allyl ether of sucrose (allyl sucrose). Copolymers are formed e.g. with minor levels of long chain alkyl acrylate co-monomers. Homopolymers are preferred. Especially preferred are carbomers 980, 940, 981 , 941 , 974, 934 and 910.
  • (e) is present in an amount of from 0.3 up to 2%.
  • Lipids form the oily phase of the emulsion-gels of the invention. They can be of a vegetable or animal nature, or partly or completely synthetic. There come into consideration lipids without ester linkages, e.g. hydrocarbons, fatty alcohols or fatty acids, and lipids having ester linkages, e.g. glycerides - i.e. fatty acid esters of glycerol -, or esters of fatty acids with C1-C36-alkanols. Hydrocarbons are e.g. paraffin or petroleum jelly. Fatty alcohols are e.g.
  • Fatty acids are e.g. C6-C24-, especially C10-C18-, alkanoic acids, e.g. hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid or octadecanoic acid.
  • Fatty acids further include unsaturated fatty acids, e.g. oleic acid or linoleic acid.
  • Glycerides are e.g.
  • esters of fatty acids with C1-C36-alkanols are e.g.
  • the lipid(s) (f) are preferably present in a total amount of 3-7, especially 4-6, % of the total composition.
  • the amount of paraffin is preferably 1.5-3%, especially 2-2.8%, and the amount of coco-caprylate/caprate is preferably 1.5-3%, especially 2-2.8%, of the total composition.
  • a non-ionic surfactant is e.g. an ester of a fatty acid, especially a C8-C18 fatty acid, with monohydroxy or, preferably, polyhydroxy compounds, e.g. ethylene glycol, glycerol, anhydrosorbitol or pentaerythritol.
  • Another important group of non-ionic surfactants is characterized by compounds having at least one active hydrogen, e.g.
  • non-ionic surfactants are partial glycerin fatty acid esters, such as glycerin monostearate; partial fatty acid esters of sorbitan or polyoxyethylene sorbitan, such as sorbitan monolaurate or polyethylene glycol (5 to 20) sorbitan monostearate or monooleate; polyoxyethylene (3 to 40) fatty alcohol ethers, such as polyoxyethylene (3 to 12) lauryl ethers or polyoxyethylene (5 to 40) cetostearyl ethers; polyoxyethylene fatty acid esters, such as polyoxyethylene (8 to 100) stearate; polyoxyethylene C4-C12-alkylphenyl ethers, e.g.
  • the non-ionic surfactant (g) is preferably present in an amount of from 1.5 up to 2.5% of the total composition.
  • Ammonia is preferably applied in the form of a concentrated aqueous solution thereof. To adjust the pH of the total composition to 6.5-8 - preferably 7-8 -, said concentrated aqueous solution of ammonia is e.g.
  • Sodium hydroxide (NaOH) and potassium hydroxide (KOH) are e.g. applied as concentrated, e.g. 30%, aqueous solutions thereof.
  • compositions of the present invention are chemically stable without a said stabilizer.
  • a further embodiment of the invention is characterized by the compositions disclosed hereinabove and hereinbefore, which compositions are devoid of a chemical stabilizer.
  • Chemical stabilizers are e.g. antioxidants or chelating agents, e.g. EDTA.
  • topical pharmaceutical compositions according to the invention are administered in a manner known per se. For example, they are applied e.g. once, twice, or three or four times daily to the affected portions of the skin.
  • the invention further relates to a method of treating inflammatory diseases which comprises topically administering to a mammal in need of such treatment a therapeutically effective amount of one of the topical pharmaceutical compositions as specified herein above and below.
  • the manufacture of the topical pharmaceutical preparations is effected in a manner known per se, for example as described in the examples below.
  • Example 1 An emulsion gel comprising 0.1% of diclofenac Na Ingredients Amount (kq/100kg.
  • Example 1a An emulsion gel comprising 0.3% of diclofenac Na is obtained in an analogous manner to Example 1 but with using 0.30 of (a), 76.0 of (b), 0.9 of (e) and 0.8 of (h) instead.
  • Example 2 An emulsion gel comprising 0.1% of diclofenac Na [without (c)]
  • Example 3 A sprayable emulsion gel (being more fluid but still opaque and homogeneous) comprising 0.1 % of diclofenac Na [without (c)]
  • the emulsion-gel is manufactured in a manner analogous to Example 1.
  • Test example 1 The stability of the emulsion gel of Example 1 is tested via an assay of diclofenac sodium. In doing so, the formulation is stored under various conditions (temperature/relative humidity) and for various storage times, and at the end the amount of diclofenac sodium still being present is determined. The results are as follows:
  • Test example 2 (microscopical examination): The emulsion gel of Example 1 is examined under 10Ox magnification and scrutinized for the presence of any crystals of diclofenac sodium. Absolutely no, not even tiny, crystals of diclofenac sodium are observed. One only sees the very fine droplets of the emulsion.

Abstract

The invention relates to beneficial topical pharmaceutical compositions comprising the diclofenac sodium salt in unusually low amounts. Said compositions represent opaque emulsion-gels, in which diclofenac is kept fully dissolved.

Description

Topical Composition
The invention concerns topical formulations comprising the well-known and widely used non- steroidal anti-inflammatory drug (NSAID) diclofenac. It is one object of the present invention to provide an advantageous emulsion-gel specifically comprising the sodium salt of diclofenac, diclofenac Na. The latter represents the most simple, cheapest, most often used (taking into account oral and other routes of administration) and best studied derivative of diclofenac.
In US patent 4,917,886, a said emulsion-gel was disclosed already [see columns 2-3, composition B)]. However, the composition given there was an experimental one only and never commercialized. Its main purpose was to provide a direct comparison with the analogous creme composition A) comprising diclofenac Na and to demonstrate the superiority of emulsion-gels over ordinary cremes. It had the following drawbacks: In order to obtain a sufficiently viscous emulsion-gel, especially in the presence of high amounts of lower alkanol (20% of isopropanol) and of an electrolyte (1% diclofenac Na), 1.2% of diethanolamine had to be used for neutralizing the gel-forming agent, polyacrylic acid (Carbopol 934 P).
However, nowadays the use of diethanolamine in topical formulations to be applied in humans is usually not recommended due to safety concerns about potential nitrosamine formation. It is therefore an object of the present invention to provide an emulsion-gel comprising diclofenac Na, which emulsion-gel can be obtained without neutralization with diethanolamine or other organic amines.
Moreover, a "true" emulsion-gel should be provided wherein diclofenac is fully dissolved (with no identifiable crystals of diclofenac being present in the formulation; see Test example 2 below) rather than partly suspended. This is crucial to guarantee a high, constant and reproducible permeation of diclofenac through the skin.
These aims have been achieved, surprisingly, by selecting specific components in specific amounts and so being able to neutralize the composition with ammonia, NaOH or KOH, in particular ammonia. The invention is further characterized in that the beneficial topical formulations provided do include diclofenac, and diclofenac Na specifically, in unusually low amounts only (<0.5%, w/w). Said low dose formulations are particularly advantageous in the topical treatment of burns including sunburn. They are providing similar relief and healing as normal dose formulations (e.g. 1%) but lead to much lower exposure of the body to the active substance.
However, in order to provide a said low dose formulation, it is essential that the latter meets extraordinary standards with regard to stability, inter alia chemical stability of the active substance. Otherwise, the amount of active substance being present in the formulation over time may fall below the limits that have to be guaranteed to ensure proper pharmaceutical activity. It is therefore another object of the invention to provide a topical composition with such an extraordinary high stability profile that allows for formulating diclofenac in low doses (see Test example 1 below).
Therefore the invention relates to a pharmaceutical composition intended for topical use, which composition is in the form of an opaque emulsion-gel and which composition comprises
(a) 0.02-0.4% (w/w) of diclofenac sodium salt,
(b) at least 50% (w/w) of water,
(c) 0-30% (w/w) of at least one C2-C4-alkanol,
(d) 3-20% (w/w) of a glycol solvent selected from the group consisting of propylene glycol and polyethylene glycol (200-20000),
(e) 0.2-3% (w/w) of at least one gelling agent selected from the group consisting of carbomers,
(f) 2-8% (w/w) of at least one lipid forming the oily phase of the emulsion-gel,
(g) 1 -5% (w/w) of at least one non-ionic surfactant, and
(h) a basic agent selected from the group consisting of ammonia, sodium hydroxide and potassium hydroxide to adjust the pH of the total composition to 6.5-8.
In one embodiment of the invention, said composition is devoid of any antifungal drug, e.g. devoid of terbinafine and topically acceptable salts thereof. In another embodiment of the invention, said composition is devoid of any further pharmaceutically active substance, that is to say, diclofenac sodium salt (a) is the only pharmaceutically active substance being present in that case. All percentages given are percentages by weight (w/w), if not indicated otherwise.
Preferred are those compositions that comprise
(a) 0.05-0.3% of diclofenac sodium salt,
(b) 60-92% of water,
(c) 0-25% of ethanol, isopropanol, or mixtures thereof,
(d) 3-20% of propylene glycol,
(e) 0.3-2% of at least one gelling agent selected from the group consisting of carbomers,
(f) 3-7% of at least one lipid forming the fatty phase of the emulsion-gel,
(g) 1-3% of at least one non-ionic surfactant, and
(h) ammonia to adjust the pH of the total composition to 6.5-8.
In one embodiment of the invention, (c) is present in an amount of from 5 up to 25% and (d) is present in an amount of from 3 up to 7%, of the total composition. In another embodiment of the invention, (c) is present (or not, respectively) in an amount of from 0 up to 5%, in particular 0%, and (d) is present in an amount of from 3 up to 20% of the total composition.
In a further embodiment of the invention, (c) is present in an amount of from 0 up to 5% and (d) is present in an amount of from 3 up to 7% of the total composition. Said emulsion-gels have the additional advantage of being perceived by patients as very pleasant and non-sticky on the skin in consumer tests. Said advantage is especially pronounced, if said compositions, in addition, comprise as component (f) isopropyl myristate, and in particular a mixture of isopropyl myristate and C6-C12-alkanoic acid C12-C18-alkyl esters.
Preferably, diclofenac Na (a) is present in amount of from 0.05 up to 0.3% - especially of from 0.1 up to 0.25% - of the total composition.
Water (b) is preferably present in an amount of from 50 up to 92%, in particular of from 60 up to 90%, or of from 60 up to 80%, of the total composition.
Preferred as C2-C4-alkanols (c) are ethanol, isopropanol, or mixtures thereof; and in particular isopropanol. Preferably, (c) is present in an amount of from 0 up to 25%, in particular of from 0 up to 20%, of the total composition. In one embodiment, (c) is typically present in an amount of from 5 up to 25%, and in particular of from 10 up to 20%, of the total composition. In another embodiment of the invention, (c) is present (or not, respectively) in an amount of from 0 up to 5% - preferably of from 0 up to 4%, more preferably of from 0 up to 3%, especially of from 0 up to 2%, and more especially of from 0 up to 1 % - of the total composition.
Preferably, the glycol solvent (d) is propylene glycol. Propylene glycol is 1 ,2-propanediol. Alternatively, polyethylene glycol (200-20000) may be used as (d), preferably polyethylene glycol (200-1000). The glycol solvent (d) is preferably present in an amount of from 3.5 up to 20%, and in particular of from 4 up to 18%, of the total composition. In one embodiment, (d) is typically present in an amount of from 3 up to 7%, and in particular of from 3.5 up to 6%, of the total composition. In another embodiment of the invention, (d) is present in an amount of from 3 up to 20%, especially of from 4 up to 18%, of the total composition.
(e) Carbomers, in the context of the present invention, are defined as homo- or copolymers of acrylic acid that are cross-linked, e.g. with an allyl ether of pentaerythritol (allyl pentaerythritol) or an allyl ether of sucrose (allyl sucrose). Copolymers are formed e.g. with minor levels of long chain alkyl acrylate co-monomers. Homopolymers are preferred. Especially preferred are carbomers 980, 940, 981 , 941 , 974, 934 and 910. In particular preferred are the following products provided by Noveon, Inc, Cleveland, Ohio, USA (formerly B F Goodrich): Carbopol® 980 and Carbopol® 974, and analogous carbomer products from other suppliers. Preferably, (e) is present in an amount of from 0.3 up to 2%.
(f) Lipids form the oily phase of the emulsion-gels of the invention. They can be of a vegetable or animal nature, or partly or completely synthetic. There come into consideration lipids without ester linkages, e.g. hydrocarbons, fatty alcohols or fatty acids, and lipids having ester linkages, e.g. glycerides - i.e. fatty acid esters of glycerol -, or esters of fatty acids with C1-C36-alkanols. Hydrocarbons are e.g. paraffin or petroleum jelly. Fatty alcohols are e.g. decanol, dodecanol, tetradecanol, hexadecanol or octadecanol. Fatty acids are e.g. C6-C24-, especially C10-C18-, alkanoic acids, e.g. hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid or octadecanoic acid. Fatty acids further include unsaturated fatty acids, e.g. oleic acid or linoleic acid. Glycerides are e.g. olive oil, castor oil, sesame oil, it being possible for all said oils also to be hydrogenated; caprylic/capric acid triglyceride or glycerol mono-, di- and tri-esters with palmitic and/or stearic acid. Esters of fatty acids with C1-C36-alkanols are e.g. beeswax, carnauba wax, cetyl palmitate, lanolin, isopropyl myristate, isopropyl stearate, oleic acid decyl ester, ethyl oleate, or C6-C12-alkanoic acid esters - especially caprylic/capric acid esters - with saturated fatty alcohols, especially C12-C18 saturated fatty alcohols.
Preferred is a mixture of paraffin - especially liquid paraffin - and C6-C12-alkanoic acid C12-C18-alkyl esters - especially caprylic/capric acid esters with C12-C18 saturated fatty alcohols (coco-caprylate/caprate, e.g. Cetiol®LC) as well as a mixture of isopropyl myristate and C6-C12-alkanoic acid C12-C18-alkyl esters (as just characterized above). The lipid(s) (f) are preferably present in a total amount of 3-7, especially 4-6, % of the total composition. If a mixture of paraffin and coco-caprylate/caprate is used, the amount of paraffin is preferably 1.5-3%, especially 2-2.8%, and the amount of coco-caprylate/caprate is preferably 1.5-3%, especially 2-2.8%, of the total composition.
(g) A non-ionic surfactant is e.g. an ester of a fatty acid, especially a C8-C18 fatty acid, with monohydroxy or, preferably, polyhydroxy compounds, e.g. ethylene glycol, glycerol, anhydrosorbitol or pentaerythritol. Another important group of non-ionic surfactants is characterized by compounds having at least one active hydrogen, e.g. fatty alcohols - especially a C8-C18 fatty alcohol -, fatty acids - especially a C8-C18 fatty acid -, sorbitan fatty acid esters, C1-Cl8-alkylphenols or C8-C18-alkylamines, that all are poly(oxyethylated), preferably with from 2 up to 40 ethylene glycol or ethylene oxide units.
Examples for the above mentioned non-ionic surfactants are partial glycerin fatty acid esters, such as glycerin monostearate; partial fatty acid esters of sorbitan or polyoxyethylene sorbitan, such as sorbitan monolaurate or polyethylene glycol (5 to 20) sorbitan monostearate or monooleate; polyoxyethylene (3 to 40) fatty alcohol ethers, such as polyoxyethylene (3 to 12) lauryl ethers or polyoxyethylene (5 to 40) cetostearyl ethers; polyoxyethylene fatty acid esters, such as polyoxyethylene (8 to 100) stearate; polyoxyethylene C4-C12-alkylphenyl ethers, e.g. polyoxyethylene (nonyl or octyl)phenyl ethers; or polyoxyethylene C8-C18-alkylamines, e.g. polyoxyethylene oleylamine. Preferred are polyoxyethylene (10 to 30) fatty alcohol ethers, in particular polyoxyethylene (20) cetostearyl ether (e.g. Cetomacrogol 1000). The non-ionic surfactant (g) is preferably present in an amount of from 1.5 up to 2.5% of the total composition. (h) Ammonia is preferably applied in the form of a concentrated aqueous solution thereof. To adjust the pH of the total composition to 6.5-8 - preferably 7-8 -, said concentrated aqueous solution of ammonia is e.g. present in an amount of 0.2-3% (w/w), especially 0.5-2% (w/w), of the total composition. Sodium hydroxide (NaOH) and potassium hydroxide (KOH) are e.g. applied as concentrated, e.g. 30%, aqueous solutions thereof.
The compositions of the inventions may optionally include further routine excipients known in the art, for example perfumes and antimicrobial preservatives, e.g. benzyl alcohol, benzalkonium chloride or parabens (= C1-C7-alkyl esters of 4-hydroxybenzoic acid, e.g. methyl 4-hydroxybenzoate).
In the experimental emulsion-gel "B)n disclosed in US patent 4,917,886, the addition of a chemical stabilizer (sodium sulphite) was necessary to provide a chemically stable formulation. In contrast thereto, the compositions of the present invention are chemically stable without a said stabilizer. In the absence of a stabilizer, e.g. the analytical work necessary to characterize the formulations and register them at the health authorities is simplified. Therefore, a further embodiment of the invention is characterized by the compositions disclosed hereinabove and hereinbefore, which compositions are devoid of a chemical stabilizer. Chemical stabilizers are e.g. antioxidants or chelating agents, e.g. EDTA.
The topical pharmaceutical compositions according to the invention are administered in a manner known per se. For example, they are applied e.g. once, twice, or three or four times daily to the affected portions of the skin.
The invention further relates to a method of treating inflammatory diseases which comprises topically administering to a mammal in need of such treatment a therapeutically effective amount of one of the topical pharmaceutical compositions as specified herein above and below.
The manufacture of the topical pharmaceutical preparations is effected in a manner known per se, for example as described in the examples below.
The following examples are intended to illustrate the invention. Example 1 : An emulsion gel comprising 0.1% of diclofenac Na Ingredients Amount (kq/100kg.
(a) diclofenac sodium salt 0.10
(b) purified water 76.57
(c) isopropanol 10.0
(d) propylene glycol 5.0
(e) Carbomer 980 0.7
(f) paraffin, liquid 2.5 (f") coco-caprylate/caprate 2.5
(g) polyoxyethylene-20-cetostearyl ether 2.0 (h) ammonia, concentrated solution in water 0.63
100.0
Manufacture: (a) is dissolved in (c), (d) and (h). Said solution is added to a mixture of (b) and (e). All remaining components - (f), (f") and (g) - are heated and slowly added to the former mixture. Upon mixing a homogeneous emulsion-gel is obtained.
Example 1a: An emulsion gel comprising 0.3% of diclofenac Na is obtained in an analogous manner to Example 1 but with using 0.30 of (a), 76.0 of (b), 0.9 of (e) and 0.8 of (h) instead.
Example 2: An emulsion gel comprising 0.1% of diclofenac Na [without (c)]
Inqredients Amount (kα/100kα.
(a) diclofenac sodium salt 0.10
(b) purified water 74.9
(c) - —
(d) propylene glycol 15.0
(e) Carbomer 974P 1.0
(f) paraffin, liquid 2.5
(f") coco-caprylate/caprate 2.5
(g) polyoxyethylene-20-cetostearyl ether 2.0
(h) 30% aqueous NaOH solution 1.5 benzyl alcohol (as preservative) 0.5
100.0 Example 3: A sprayable emulsion gel (being more fluid but still opaque and homogeneous) comprising 0.1 % of diclofenac Na [without (c)]
Ingredients Amount (kg/100kα)
(a) diclofenac sodium salt 0.10
(b) purified water 86.68
(c) -
(d) propylene glycol 5.0
(e) Carbomer 974P 0.3
(f) paraffin, liquid 2.5 (f") coco-caprylate/caprate 2.5
(g) polyoxyethylene-20-cetostearyl ether 2.0 (h) 30% aqueous NaOH solution 0.42 benzyl alcohol (as preservative) 0.5
100.0 The emulsion-gel is manufactured in a manner analogous to Example 1.
Test example 1 : The stability of the emulsion gel of Example 1 is tested via an assay of diclofenac sodium. In doing so, the formulation is stored under various conditions (temperature/relative humidity) and for various storage times, and at the end the amount of diclofenac sodium still being present is determined. The results are as follows:
Figure imgf000009_0001
It is demonstrated that the active substance is completely stable even under demanding storage conditions for long periods of time.
Test example 2 (microscopical examination): The emulsion gel of Example 1 is examined under 10Ox magnification and scrutinized for the presence of any crystals of diclofenac sodium. Absolutely no, not even tiny, crystals of diclofenac sodium are observed. One only sees the very fine droplets of the emulsion.

Claims

Claims
1. A pharmaceutical composition intended for topical use, which composition is in the form of an opaque emulsion-gel and which composition comprises
(a) 0.02-0.4% (w/w) of diclofenac sodium salt,
(b) at least 50% (w/w) of water,
(c) 0-30% (w/w) of at least one C2-C4-alkanol,
(d) 3-20% (w/w) of a glycol solvent selected from the group consisting of propylene glycol and polyethylene glycol (200-20000),
(e) 0.2-3% (w/w) of at least one gelling agent selected from the group consisting of carbomers,
(f) 2-8% (w/w) of at least one lipid forming the oily phase of the emulsion-gel,
(g) 1 -5% (w/w) of at least one non-ionic surfactant, and
(h) a basic agent selected from the group consisting of ammonia, sodium hydroxide and potassium hydroxide to adjust the pH of the total composition to 6.5-8; with the proviso that said composition is devoid of an antifungal drug.
2. A composition according to claim 1 , which comprises
(a) 0.05-0.3% of diclofenac sodium salt,
(b) 60-92% of water,
(c) 0-25% of ethanol, isopropanol, or mixtures thereof,
(d) 3-20% of propylene glycol,
(e) 0.3-2% of at least one gelling agent selected from the group consisting of carbomers,
(f) 3-7% of at least one lipid forming the fatty phase of the emulsion-gel,
(g) 1-3% of at least one non-ionic surfactant, and
(h) ammonia to adjust the pH of the total composition to 6.5-8.
3. A pharmaceutical composition intended for topical use, which composition is in the form of an opaque emulsion-gel and which composition consists essentially of
(a) 0.02-0.4% (w/w) of diclofenac sodium salt,
(b) at least 50% (w/w) of water,
(c) 0-30% (w/w) of at least one C2-C4-alkanol,
(d) 3-20% (w/w) of a glycol solvent selected from the group consisting of propylene glycol and polyethylene glycol (200-20000), (e) 0.2-3% (w/w) of at least one gelling agent selected from the group consisting of carbomers,
(f) 2-8% (w/w) of at least one lipid forming the oily phase of the emulsion-gel,
(g) 1-5% (w/w) of at least one non-ionic surfactant, and
(h) a basic agent selected from the group consisting of ammonia, sodium hydroxide and potassium hydroxide to adjust the pH of the total composition to 6.5-8.
4. A composition according to claim 1 or claim 3, wherein the polyethylene glycol (200-20000) usable as component (d) is polyethylene glycol (200-1000).
5. A composition according to any one of claims 1-4, which comprises (c) in an amount of from 5 up to 25% and (d) in an amount of from 3 up to 7% of the total composition.
6. A composition according to any one of claims 1-4, which comprises (c) in an amount of from 0 up to 5% and (d) in an amount of from 3 up to 20% of the total composition.
7. A composition according to any one of claims 1 -4, which comprises (c) in an amount of from 0 up to 5% and (d) in an amount of from 3 up to 7% of the total composition.
8. A composition according to claim 6 or claim 7, which is devoid of the component (c).
9. A composition according to any one of claims 1 -7, which comprises as C2-C4-alkanol (c) isopropanol.
10. A composition according to any one of claims 1-9, which comprises as gelling agent (e) carbomer 980, carbomer 940, carbomer 981 , carbomer 941 , carbomer 974, carbomer 934, carbomer 910, or a mixture of any of said carbomers.
11. A composition according to any one of claims 1 -10, which comprises as lipid (f) either a mixture of paraffin and C6-C12-alkanoic acid C12-C18-alkyl esters, or a mixture of isopropyl myristate and C6-C12-alkanoic acid C12-C18-alkyl esters.
12. A composition according to any one of claims 5-7, which comprises as lipid (f) isopropyl myristate.
13. A composition according to any one of claims 1-12, which comprises as non-ionic surfactant (g) a polyoxyethylene (10 to 30) fatty alcohol ether.
14. A composition according to any one of claims 1-13, which is devoid of a chemical stabilizer.
PCT/EP2003/009302 2002-08-22 2003-08-21 Topical emulsion- gel composition comprising diclofenac sodium WO2004017998A2 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
MXPA05002077A MXPA05002077A (en) 2002-08-22 2003-08-21 Topical emulsion- gel composition comprising diclofenac sodium.
DE60319997T DE60319997T2 (en) 2002-08-22 2003-08-21 TOPICAL EMULSION PREPARATION CONTAINED DICLOFENAC SODIUM
EP03792412A EP1536836B1 (en) 2002-08-22 2003-08-21 Topical emulsion- gel composition comprising diclofenac sodium
US10/524,735 US7732489B2 (en) 2002-08-22 2003-08-21 Topical emulsion-gel composition comprising diclofenac sodium
CA2496469A CA2496469C (en) 2002-08-22 2003-08-21 Topical emulsion-gel composition comprising diclofenac sodium
DK03792412T DK1536836T3 (en) 2002-08-22 2003-08-21 Topical emulsion gel composition containing diclofenac sodium
BR0313701-5A BR0313701A (en) 2002-08-22 2003-08-21 Topical emulsion gel composition comprising diclofenac sodium
AU2003264086A AU2003264086B2 (en) 2002-08-22 2003-08-21 Topical emulsion- gel composition comprising diclofenac sodium
SI200331225T SI1536836T1 (en) 2002-08-22 2003-08-21 Topical emulsion- gel composition comprising diclofenac sodium
US12/778,322 US8557870B2 (en) 2002-08-22 2010-05-12 Methods of treatment utilizing topical emulsion-gel composition comprising diclofenac sodium
US14/053,176 US8716340B2 (en) 2002-08-22 2013-10-14 Topical composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP02018772 2002-08-22
EP02018772.0 2003-08-22

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US10/524,735 A-371-Of-International US7732489B2 (en) 2002-08-22 2003-08-21 Topical emulsion-gel composition comprising diclofenac sodium
US52473503A A-371-Of-International 2003-08-21 2003-08-21
US12/778,322 Continuation US8557870B2 (en) 2002-08-22 2010-05-12 Methods of treatment utilizing topical emulsion-gel composition comprising diclofenac sodium

Publications (2)

Publication Number Publication Date
WO2004017998A2 true WO2004017998A2 (en) 2004-03-04
WO2004017998A3 WO2004017998A3 (en) 2004-04-01

Family

ID=31896841

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/009302 WO2004017998A2 (en) 2002-08-22 2003-08-21 Topical emulsion- gel composition comprising diclofenac sodium

Country Status (16)

Country Link
US (3) US7732489B2 (en)
EP (1) EP1536836B1 (en)
AR (1) AR041021A1 (en)
AT (1) ATE390149T1 (en)
AU (1) AU2003264086B2 (en)
BR (1) BR0313701A (en)
CA (1) CA2496469C (en)
DE (1) DE60319997T2 (en)
DK (1) DK1536836T3 (en)
ES (1) ES2300645T3 (en)
MX (1) MXPA05002077A (en)
PE (1) PE20040321A1 (en)
PT (1) PT1536836E (en)
SI (1) SI1536836T1 (en)
TW (1) TWI316857B (en)
WO (1) WO2004017998A2 (en)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1588697A1 (en) * 2004-04-16 2005-10-26 Kurt H. Prof. Dr. Bauer Emulsion gel for topical application of pharmaceuticals
WO2006089804A1 (en) * 2005-02-25 2006-08-31 Galderma S.A. Aqueous topical gel of high stability based on metronidazole and method of preparation
WO2006116661A2 (en) * 2005-04-27 2006-11-02 Avocet Polymer Technologies, Inc. Polyethylene glycol based composition for topical treatment of a closed wound with therapeutic pharmaceuticals
WO2008110741A2 (en) * 2007-03-13 2008-09-18 Futura Medical Developments Limited Topical pharmaceutical formulation
WO2009012908A2 (en) * 2007-07-26 2009-01-29 Bayer Animal Health Gmbh Medicament for transdermal use on animals
WO2010045415A2 (en) * 2008-10-16 2010-04-22 Novartis Ag Topical nsaid compositions having sensate component
WO2010089046A1 (en) * 2009-02-09 2010-08-12 Doris Barnikol-Keuten In situ preparations forming bonding gel, in particular for topical application to moistened skin/mucous membranes
WO2014009793A1 (en) 2012-07-11 2014-01-16 Glycores 2000 S.R.L. Diclofenac solution for external use
US9066913B2 (en) 2006-10-17 2015-06-30 Hznp Limited Diclofenac topical formulation
US9132110B2 (en) 2009-03-31 2015-09-15 Hznp Limited Treatment of pain with topical diclofenac
WO2016132159A1 (en) * 2015-02-20 2016-08-25 Futura Medical Developments Limited Topical pharmaceutical formulation
EP2214642B1 (en) 2007-10-30 2017-05-03 Novartis Consumer Health S.A. Topical composition
US11000495B2 (en) 2014-09-10 2021-05-11 GSK Consumer Healthcare S.A. Topical diclofenac sodium compositions
WO2023180792A1 (en) 2022-03-25 2023-09-28 Glycores 2000 Srl Topical pharmaceutical composition with anti-inflammatory and analgesic activity and uses thereof

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010502764A (en) * 2006-09-11 2010-01-28 バイオマス リミテッド Topical formulation of tellurium-containing compounds
US20100100060A1 (en) * 2008-10-17 2010-04-22 Novartis Ag Applicator for pharmaceutical product and method of using same
US8546450B1 (en) 2009-03-31 2013-10-01 Nuvo Research Inc. Treatment of pain with topical diclofenac compounds
AU2010233343A1 (en) 2009-04-08 2011-10-27 Cadila Healthcare Limited Stable pharmaceutical compositions of diclofenac
BR112012014558B8 (en) * 2009-12-16 2021-05-25 Shasun Pharmaceuticals Ltd new dexibuprofen transdermal hydrogel composition
WO2013014680A1 (en) 2011-07-28 2013-01-31 Cadila Healthcare Limited Method for treatment of pain and inflammation
CA2878784A1 (en) 2012-07-12 2014-01-16 Ferring B.V. Diclofenac formulations
JP6598619B2 (en) * 2015-09-28 2019-10-30 株式会社ポーラファルマ Skin external preparation specified by physical properties
FR3064495B1 (en) 2017-03-31 2021-04-02 Total Marketing Services UREA-BASED COMPOSITION FOR THE TREATMENT OF EXHAUST GASES
WO2023052599A1 (en) 2021-10-01 2023-04-06 Nutrition & Biosciences Usa 1, Llc Hydrocolloid blend compositions for topical application

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4917886A (en) * 1982-10-07 1990-04-17 Ciba-Geigy Corporation Novel topically administrable pharmaceutical compositions
US5350769A (en) * 1990-10-30 1994-09-27 Ss Pharmaceutical Co., Ltd. Antiinflammatory gel preparation
WO2002078648A2 (en) * 2001-03-30 2002-10-10 Novartis Consumer Health S.A. Topical composition comprising an antifungal

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2112751A1 (en) * 1991-07-03 1993-01-21 Charles J. Ii Betlach Composition and method for transdermal delivery of diclofenac
US5399342A (en) * 1993-02-03 1995-03-21 Dow Corning Corporation Cosmetics with enhanced durability
EP0879597A4 (en) * 1996-02-07 2001-01-31 Tsumura & Co Transparent aqueous solution of diclofenac sodium and medicinal compositions with the use of the same
DE69819748T2 (en) * 1997-09-12 2004-09-30 Columbia Laboratories (Bermuda) Ltd. MEDICINES FOR TREATING DYSMENORRHEA AND PREVIOUS BLIES
TWI290464B (en) 2000-09-01 2007-12-01 Novartis Consumer Health Sa Treatment of burns

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4917886A (en) * 1982-10-07 1990-04-17 Ciba-Geigy Corporation Novel topically administrable pharmaceutical compositions
US5350769A (en) * 1990-10-30 1994-09-27 Ss Pharmaceutical Co., Ltd. Antiinflammatory gel preparation
WO2002078648A2 (en) * 2001-03-30 2002-10-10 Novartis Consumer Health S.A. Topical composition comprising an antifungal

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1588697A1 (en) * 2004-04-16 2005-10-26 Kurt H. Prof. Dr. Bauer Emulsion gel for topical application of pharmaceuticals
WO2006089804A1 (en) * 2005-02-25 2006-08-31 Galderma S.A. Aqueous topical gel of high stability based on metronidazole and method of preparation
WO2006116661A2 (en) * 2005-04-27 2006-11-02 Avocet Polymer Technologies, Inc. Polyethylene glycol based composition for topical treatment of a closed wound with therapeutic pharmaceuticals
WO2006116661A3 (en) * 2005-04-27 2007-03-29 Avocet Polymer Technologies In Polyethylene glycol based composition for topical treatment of a closed wound with therapeutic pharmaceuticals
US9539335B2 (en) 2006-10-17 2017-01-10 Hznp Limited Diclofenac topical formulation
US9066913B2 (en) 2006-10-17 2015-06-30 Hznp Limited Diclofenac topical formulation
US9168305B2 (en) 2006-10-17 2015-10-27 Hznp Limited Diclofenac topical formulation
US9339551B2 (en) 2006-10-17 2016-05-17 Hznp Limited Diclofenac topical formulation
US9220784B2 (en) 2006-10-17 2015-12-29 Hznp Limited Diclofenac topical formulation
US9339552B2 (en) 2006-10-17 2016-05-17 Hznp Limited Diclofenac topical formulation
US9101591B2 (en) 2006-10-17 2015-08-11 Hznp Limited Diclofenac topical formulation
US9168304B2 (en) 2006-10-17 2015-10-27 Hznp Limited Diclofenac topical formulation
JP2010521442A (en) * 2007-03-13 2010-06-24 フューチュラ メディカル ディベロップメンツ リミテッド Topical formulation
WO2008110741A2 (en) * 2007-03-13 2008-09-18 Futura Medical Developments Limited Topical pharmaceutical formulation
RU2468794C2 (en) * 2007-03-13 2012-12-10 Футура Медикал Дивелэпментс Лимитед Pharmaceutical composition for topic application
AU2008224735B2 (en) * 2007-03-13 2013-04-18 Futura Medical Developments Limited Topical pharmaceutical formulation
US8541470B2 (en) 2007-03-13 2013-09-24 Futura Medical Developments Limited Topical pharmaceutical formulation
WO2008110741A3 (en) * 2007-03-13 2009-03-12 Futura Medical Dev Ltd Topical pharmaceutical formulation
WO2009012908A2 (en) * 2007-07-26 2009-01-29 Bayer Animal Health Gmbh Medicament for transdermal use on animals
WO2009012908A3 (en) * 2007-07-26 2009-06-11 Bayer Animal Health Gmbh Medicament for transdermal use on animals
DE102007034976A1 (en) 2007-07-26 2009-01-29 Bayer Healthcare Ag Medicinal products for transdermal use in animals
EP2214642B1 (en) 2007-10-30 2017-05-03 Novartis Consumer Health S.A. Topical composition
WO2010045415A2 (en) * 2008-10-16 2010-04-22 Novartis Ag Topical nsaid compositions having sensate component
JP2012505909A (en) * 2008-10-16 2012-03-08 ノバルティス アーゲー Topical NSAID composition with sensory components
WO2010045415A3 (en) * 2008-10-16 2010-06-10 Novartis Ag Topical nsaid compositions having sensate component
WO2010089046A1 (en) * 2009-02-09 2010-08-12 Doris Barnikol-Keuten In situ preparations forming bonding gel, in particular for topical application to moistened skin/mucous membranes
US10058519B2 (en) 2009-03-31 2018-08-28 Hznp Limited Treatment of pain with topical diclofenac
US9370501B2 (en) 2009-03-31 2016-06-21 Hznp Limited Treatment of pain with topical diclofenac
US9375412B2 (en) 2009-03-31 2016-06-28 Hznp Limited Treatment of pain with topical diclofenac
US9415029B2 (en) 2009-03-31 2016-08-16 Hznp Limited Treatment of pain with topical diclofenac
US9132110B2 (en) 2009-03-31 2015-09-15 Hznp Limited Treatment of pain with topical diclofenac
WO2014009793A1 (en) 2012-07-11 2014-01-16 Glycores 2000 S.R.L. Diclofenac solution for external use
US11000495B2 (en) 2014-09-10 2021-05-11 GSK Consumer Healthcare S.A. Topical diclofenac sodium compositions
WO2016132159A1 (en) * 2015-02-20 2016-08-25 Futura Medical Developments Limited Topical pharmaceutical formulation
US10028927B2 (en) 2015-02-20 2018-07-24 Futura Medical Developments Limited Topical pharmaceutical formulation
WO2023180792A1 (en) 2022-03-25 2023-09-28 Glycores 2000 Srl Topical pharmaceutical composition with anti-inflammatory and analgesic activity and uses thereof

Also Published As

Publication number Publication date
EP1536836B1 (en) 2008-03-26
BR0313701A (en) 2005-06-28
PT1536836E (en) 2008-05-09
CA2496469C (en) 2011-07-05
DE60319997D1 (en) 2008-05-08
SI1536836T1 (en) 2008-08-31
ATE390149T1 (en) 2008-04-15
DE60319997T2 (en) 2009-04-30
US7732489B2 (en) 2010-06-08
US20140045942A1 (en) 2014-02-13
TWI316857B (en) 2009-11-11
DK1536836T3 (en) 2008-07-21
EP1536836A2 (en) 2005-06-08
US8716340B2 (en) 2014-05-06
PE20040321A1 (en) 2004-07-15
US20050239894A1 (en) 2005-10-27
TW200409646A (en) 2004-06-16
AU2003264086B2 (en) 2007-01-04
WO2004017998A3 (en) 2004-04-01
AU2003264086A1 (en) 2004-03-11
MXPA05002077A (en) 2005-06-08
CA2496469A1 (en) 2004-03-04
US20100234462A1 (en) 2010-09-16
US8557870B2 (en) 2013-10-15
ES2300645T3 (en) 2008-06-16
AR041021A1 (en) 2005-04-27

Similar Documents

Publication Publication Date Title
US8716340B2 (en) Topical composition
AU2008317737B2 (en) Topical composition
CA2776471C (en) Surfactant-free, water-free, foamable compositions and breakable foams and their uses
ES2654407T3 (en) Semi-solid aqueous pharmaceutical composition containing tapentadol
JP6077350B2 (en) Topical pharmaceutical composition for atopic dermatitis containing clobetasone butyrate
US20230037905A1 (en) Topical composition comprising tofacitinib and fingolimod
WO2021178834A1 (en) Topical pharmaceutical formulations of a cyclic depsipeptide
CN100490899C (en) Pharmaceutical compositions

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LT LU LV MA MD MK MN MX NI NO NZ OM PG PH PL PT RO RU SC SE SG SK SY TJ TM TN TR TT UA US UZ VC VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2003792412

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2003264086

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 10524735

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2496469

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2005/002077

Country of ref document: MX

WWP Wipo information: published in national office

Ref document number: 2003792412

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP

WWG Wipo information: grant in national office

Ref document number: 2003264086

Country of ref document: AU

WWG Wipo information: grant in national office

Ref document number: 2003792412

Country of ref document: EP